Plasmin generation induces neutrophil aggregation: Dependence on the catalytic and lysine binding sites

Ryan, Thomas J.; Lai, Linda; Malik, Asrar B.

doi:10.1002/jcp.1041510206

Cited by 27 publications

(25 citation statements)

References 20 publications

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“…Thereby, cell-associated plasmin might promote cellular migration (10). Indeed, plasmin-induced neutrophil aggregation and adhesion in vitro (46,47). Moreover, studies using Plg Ϫ/Ϫ mice have provided in vivo evidence for an essential role of the plasminogen system in thioglycolate-induced macrophage migration (21).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

Renckens

Roelofs

Florquin

et al. 2006

The Journal of Immunology

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Sepsis is associated with enhanced production of tissue-type plasminogen activator (tPA). We investigated the function of endogenous tPA in the immune responses to Escherichia coli-induced abdominal sepsis using tPA gene-deficient (tPA−/−) and normal wild-type (WT) mice. tPA−/− mice demonstrated an impaired defense against E. coli peritonitis as indicated by higher bacterial loads at the primary site of the infection, enhanced dissemination, and reduced survival. The protective function of tPA was independent of plasmin since plasminogen gene-deficient (Plg−/−) mice were indistinguishable from WT mice. Relative to WT mice, tPA−/− mice demonstrated similar neutrophil counts in the peritoneal cavity despite much higher bacterial loads and higher local concentrations of neutrophil attracting chemokines, suggesting a reduced migratory response. In line, tPA−/− mice demonstrated a reduced thioglycolate-induced neutrophil influx into the peritoneal cavity and i.p. injection of WT mice with a replication-defective adenoviral vector expressing tPA caused an enhanced cell migration to the peritoneal cavity during E. coli peritonitis. These findings identify a novel protective function of tPA in abdominal sepsis caused by E. coli that seems independent of its role in the generation of plasmin.

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Section: Discussionmentioning

confidence: 99%

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

Renckens

Roelofs

Florquin

et al. 2006

The Journal of Immunology

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“…33 Plasmin induced neutrophil aggregation and increased neutrophil adhesion to endothelial cells in vitro, an effect that could be inhibited by tranexamic acid. 19,20,27 The plasmin-induced neutrophil adherence was mediated through an upregulation of CD18 neutrophil cell surface glycoprotein, reflecting neutrophil activation. These data suggest that plasmin is able to activate neutrophils, which can be abrogated by tranexamic acid.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, plasmin was demonstrated to stimulate the release of cytokines and other inflammatory mediators by different cell types. [13][14][15][16] Furthermore, plasmin induced cell adhesion and migration in vitro, [17][18][19][20] and studies using plasminogen-deficient mice have provided in vivo evidence for an essential role of the plasminogen system in cell migration toward inflammatory sites. 21,22 Moreover, plasmin can activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway in monocytes, 14,23 and activation of this pathway was recently shown to be of key importance for the inflammatory response to LPS in humans.…”

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confidence: 99%

“…26 In vitro, tranexamic acid potently inhibited plasmin-induced proinflammatory responses. 13,19,27 The fact that the formation of plasmin is one of the earliest-occurring events after intravenous administration of LPS, together with the recent findings that plasmin is able to induce several cellular proinflammatory responses, including activation of p38 MAPK, led us to hypothesize that plasmin may play a role in the induction of LPS-induced inflammatory pathways. To test this hypothesis, we studied the effect of tranexamic acid infusion on activation of coagulation, granulocytes, endothelial cells, and the cytokine network in healthy humans injected with a single dose of LPS.…”

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confidence: 99%

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Inhibition of Plasmin Activity by Tranexamic Acid Does Not Influence Inflammatory Pathways During Human Endotoxemia

Renckens

Weijer

Vos

et al. 2004

ATVB

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Objective-Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems. Methods and Results-To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (from Escherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, nϭ8), a plasmin activation inhibitor, or placebo (nϭ8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-␣2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (both PϽ0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-␣1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release. Conclusion-These

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“…In addition to its proteolytic effects, plasmin is known to activate the complement system (1,12,16,33), which in turn can lead to an extension of reperfusion injury (18,19). In addition, plasmin increases the synthesis of leukotriene B4 (41), cytokines (IL-1␣, IL-1␤, TNF-␣), and tissue factor (TF) expression (35); and directly influences platelet reactivity (31,32), neutrophils (30), and endothelial cells (9). Extension of tissue injury induced by plasmin and rt-PA was observed in rat brain tissue (24,44).…”

Section: Discussionmentioning

confidence: 99%

Effect of thrombolysis on myocardial injury: recombinant tissue plasminogen activator vs. alfimeprase

Hong

Huang

Lucchesi

2006

American Journal of Physiology-Heart and Circulatory Physiology

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dependent thrombolytic agents are potentially prothrombotic and proinflammatory. Alfimeprase, a zinc-containing metalloproteinase, degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This study examines the hypothesis that thrombolysis in the absence of plasmin generation results in improved myocardial salvage on reperfusion. The thrombolytic effects of recombinant tissue plasminogen activator [rt-PA; 0.022 mg/kg, 1/10 of which was administered as a loading dose; the rest (9/10) was infused over 60 min by intracoronary (ic) administration] or alfimeprase (0.5 mg/kg over 1 min ic) were evaluated in a canine model of arterial thrombosis involving electrolytic injury of the left circumflex (LCX) coronary artery. Both agents induced thrombolysis, with onset of reperfusion being more rapid after alfimeprase compared with rt-PA (1.5 Ϯ 0.6 vs. 10.1 Ϯ 2.1 min). In the absence of adjunctive therapy, time to reocclusion after alfimeprase was 3.2 Ϯ 0.5 min compared with 77.5 Ϯ 31.9 min with rt-PA. The glycoprotein IIb/IIIa platelet receptor antagonist CRL-42796 prolonged reperfusion time after thrombolysis with alfimeprase or rt-PA. The effect of each lytic agent on myocardial infarct size was examined in a separate group of dogs subjected to 60 min of LCX coronary artery ligation and 4 h of reperfusion. Myocardial infarct size, expressed as percentage of the risk region, was larger (32.16 Ϯ 3.95%) after rt-PA compared with alfimeprase (19.85 Ϯ 3.61%) or that of the saline control group (18.46 Ϯ 3.34%). rt-PA in contrast to alfimeprase, a direct-acting fibrinolytic agent, is associated with an increase in myocyte reperfusion injury. myocardium; reperfusion injury; thrombolytic agents THROMBOLYTIC AGENTS in current use activate the fibrinolytic system and achieve thrombolysis through the conversion of plasminogen to plasmin. In addition to its well-characterized mechanism of action on clot lysis, plasmin directly activates other enzymatic systems that contribute to proinflammatory events that may compromise the overall benefits of lytic therapy.Previous studies document the induction of platelet activation by plasmin and plasmin-dependent thrombolytic agents (4, 26), while others have shown both activation as well as inhibitory effects (6, 27). Therapeutic reperfusion, achieved by intravenous administration of recombinant tissue plasminogen activator (rt-PA), is effective in salvaging tissue at risk of irreversible ischemic injury. The benefit of lytic therapy, however, may be limited because of failed reperfusion in 25-40% of the patients (40, 42) and the high incidence (30%) of reocclusion (43). Furthermore, because of the activation of the plasminogen-plasmin system, the mechanism for the cardioprotective effect of thrombolytic therapy remains unresolved (20).Myocardial ischemia of sufficient duration, followed by reperfusion, is associated with an extension of irreversible tissue injury. The ensuing myocyte cell death is attributed to both the ischemic episode as well as to undefined cov...

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Plasmin generation induces neutrophil aggregation: Dependence on the catalytic and lysine binding sites

Cited by 27 publications

References 20 publications

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

Inhibition of Plasmin Activity by Tranexamic Acid Does Not Influence Inflammatory Pathways During Human Endotoxemia

Effect of thrombolysis on myocardial injury: recombinant tissue plasminogen activator vs. alfimeprase

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